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KSR Number: KSRA20063

Fresh versus frozen embryo transfers in assisted reproduction

  • Cochrane Database Syst Rev 2017, 3, CD011184, 10.1002/14651858.CD011184.pub2
  • Full report

Risk of Bias Assessment

Overall summary: Low risk of bias in the review

Bottom Line

Current evidence suggests there is no difference in terms of live birth rates or ongoing pregnancy rates for freeze-all vs. conventional embryo transfer strategies in assisted reproduction. The freeze-all embryo transfer strategy may be associated with a lower rate of ovarian hyperstimulation syndrome and a lower miscarriage rate, but a higher pregnancy complication rate compared to conventional embryo transfer strategy. While the review had no significant methodological weaknesses, restrictions based on publication format mean some studies may have been missed. Further well-designed randomised clinical trials focused on the cumulative live birth rate and ovarian hyperstimulation syndrome per hyperstimulated cycle are needed.

Risk of Bias Assessment

Overall summary Low risk of bias in the review

Low

Restrictions were reported based on publication format (trials published only as an abstract were excluded), meaning some studies may have been missed. Overall, all domains were considered at low concern.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Probably yes
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review Low

Details of Review

Number of studies 4
Number of participants 1,892
Last search date November 2016
Review type Intervention
Objective To evaluate the effectiveness and safety of the freeze-all strategy compared to the conventional in vitro fertilisation/intracytoplasmic sperm injection strategy in women undergoing assisted reproductive technology.
Population All women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).
Interventions Freeze-all strategy with transfer of frozen-thawed embryos only.
Comparator Conventional IVF/ICSI strategy with transfer of fresh and subsequent frozen-thawed embryos until a live birth occurred or until all embryos from the initial cycle were transferred.
Outcome Primary outcomes: effectiveness (cumulative live birth rate per randomised woman) and safety (ovarian hyperstimulation syndrome per randomised woman).

Secondary outcomes: cumulative ongoing pregnancy rate, clinical pregnancy, time to pregnancy, multiple-pregnancy rate, miscarriage rate, pregnancy complications, birth weight of babies born per baby, congenital disorders, multiple pregnancies per clinical pregnancy, miscarriage per clinical pregnancy, pregnancy complications per clinical pregnancy and birth weight per clinical pregnancy.
Study design Randomised clinical trials.

Quasi- and pseudo-randomised clinical trials were excluded.

Results

Outcomes per woman:

In terms of live birth rates per woman, pooled analyses reported no significant difference between conventional versus freeze-all embryo transfer (odds ratio [OR] 1.09, 95% confidence interval [CI] 0.91 to 1.31, four trials, n=1,892 women). In subgroup analysis based on the timing of embryo transfer (cleavage stage versus blastocyst stage), there was no difference between timing of transfer (OR 1.11, 95% CI 0.91 to 1.35, two trials, n=1,633 women versus OR 0.99, 95% CI 0.60 to 1.62, two trials, n=259 women).

In terms of rates of ovarian hyperstimulation syndrome (OHSS) per woman, pooled analyses reported a significantly lower rate for freeze-all versus conventional embryo transfer (Peto odds ratio [pOR] 0.24, 95% CI 0.15 to 0.38, two trials, n=1,633 women). This translated into a reported absolute risk of 18 per 1,000 women for the freeze-all embryo transfer compared to 70 per 1,000 women for the conventional embryo transfer.

In terms of miscarriage rates per woman after the first embryo transfer, pooled analyses reported a significantly lower rate of miscarriage for freeze-all versus conventional embryo transfer (OR 0.67, 95% CI 0.52 to 0.86, four trials, n=1,892 women). This translated into a reported absolute risk of 131 per 1,000 women for the freeze-all embryo transfer compared to 184 per 1,000 women for the conventional embryo transfer.

Birth weight per woman was analysed by subgroups based on singleton or multiple births. A single trial reported a higher birth weight of singleton babies with the freeze-all versus conventional embryo transfer method (mean difference [MD] 161.80, 95% CI 57.11 to 266.49, one trial, n=462 women), but no significant difference in the birth weight of multiple babies (MD -2.00, 95% CI -94.08 to 90.08, one trial, n=453 women).

In terms of pregnancy complications per woman after the first embryo transfer, pooled analyses reported a significantly higher pregnancy complication rate for freeze-all versus conventional embryo transfer (pOR 1.44, 95% CI 1.08 to 1.92, two trials, n=1,633 women). This translated into a reported absolute risk of 151 per 1,000 women for the freeze-all embryo transfer compared to 110 per 1,000 women for the conventional embryo transfer.

In terms of ongoing pregnancy rates per woman, pooled analyses reported no significant difference between conventional versus freeze-all embryo transfer (OR 1.05, 95% CI 0.64 to 1.73, two trials, n=259 women).

In terms of multiple pregnancies per woman after the first embryo transfer, pooled analyses reported no significant difference between conventional versus freeze-all embryo transfer (OR 1.11, 95% CI 0.85 to 1.44, two trials, n=1,630 women).

In terms of clinical pregnancy rates per woman, a single trial reported no significant difference between conventional versus freeze-all embryo transfer (OR 1.08, 95% CI 0.54 to 2.19, one trial, n=125 women).

Outcomes per clinical pregnancy:

In terms of miscarriage rates per clinical pregnancy after the first embryo transfer, pooled analysis reported a significantly lower rate with freeze-all versus conventional embryo transfer (OR 0.56, 95% CI 0.41 to 0.77; four trials; n=1,058 clinical pregnancies).

In terms of pregnancy complications per clinical pregnancy after the first embryo transfer, pooled analyses reported more pregnancy complications with freeze-all versus conventional embryo transfer (OR 1.43, 95% CI 1.05 to 1.95, two trials, n=914 clinical pregnancies).

In terms of multiple pregnancies per clinical pregnancy after the first embryo transfer, pooled analyses reported no significant difference between conventional versus freeze-all embryo transfer (OR 1.02, 95% CI 0.77 to 1.37, two trials, n=939 clinical pregnancies).

Outcomes per live-born children plus foetuses therapeutically terminated:

In terms of congenital abnormalities, a single study reported no significant difference between conventional versus freeze-all embryo transfer (OR 1.25, 95% CI 0.66 to 2.37, one trial, n=923 women).

Full Risk of Bias Assessment

The research objective was clearly stated. The eligibility criteria were well described and appeared appropriate to address the review question. Restrictions were reported based on publication format (trials published only as an abstract were excluded). No restrictions were applied based on the language or date.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Probably yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Probably no
Concerns regarding specification of study eligibility criteria Low

Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies (CENTRAL CRSO), MEDLINE, EMBASE, PsycINFO, CINAHL, ClinicalTrials.gov, the World Health Organisation International Clinical Trials Registry Platform, Database of Abstracts of Reviews of Effects (DARE) in the Cochrane Library, conference abstracts in the Web of Knowledge, OpenGrey (System for Information on Grey Literature in Europe) and PubMed were searched. The reference lists of eligible articles, relevant journals and conference abstracts were handsearched to identify additional relevant studies. The study authors were contacted for additional details, where necessary. The search strategy was reported in full and appeared to be adequate. Searches were not restricted by the date, publication format or language. Two review authors were independently involved in the study selection and any disagreements were resolved by discussion or by consultation with a third review author.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Yes
2.2 Were methods additional to database searching used to identify relevant reports? Probably yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably yes
2.4 Were restrictions based on date, publication format, or language appropriate? Probably yes
2.5 Were efforts made to minimise error in selection of studies? Yes
Concerns regarding methods used to identify and/or select studies Low

Two review authors independently performed the data extraction and any discrepancies were resolved by discussion. Sufficient study characteristics appear to have been extracted to allow interpretation of the results. Two reviewers independently assessed quality of the included studies using the Cochrane risk of bias assessment tool.

3.1 Were efforts made to minimise error in data collection? Yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably yes
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Probably yes
3.5 Were efforts made to minimise error in risk of bias assessment? Yes
Concerns regarding methods used to collect data and appraise studies Low

The synthesis appeared to include all eligible studies. The method of analysis was explained and appeared appropriate. Study heterogeneity was assessed and found to be significant for one outcome (pregnancy complications). Sensitivity analysis was performed to test the robustness of findings. The quality of the individual studies was considered in the synthesis.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Probably yes
Concerns regarding synthesis and findings Low

Abstract

Background: In general, in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) implies a single fresh and one or more frozen-thawed embryo transfers. Alternatively, the 'freeze-all' strategy implies transfer of frozen-thawed embryos only, with no fresh embryo transfers. In practice, both strategies can vary technically including differences in freezing techniques and timing of transfer of cryopreservation, that is vitrification versus slow freezing, freezing of two pro-nucleate (2pn) versus cleavage-stage embryos versus blastocysts, and transfer of cleavage-stage embryos versus blastocysts.In the freeze-all strategy, embryo transfers are disengaged from ovarian stimulation in the initial treatment cycle. This could avoid a negative effect of ovarian hyperstimulation on the endometrium and thereby improve embryo implantation. It could also reduce the risk of ovarian hyperstimulation syndrome (OHSS) in the ovarian stimulation cycle by avoiding a pregnancy.We compared the benefits and risks of the two treatment strategies.Objectives: To evaluate the effectiveness and safety of the freeze-all strategy compared to the conventional IVF/ICSI strategy in women undergoing assisted reproductive technology.Search methods: We searched the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Studies (CRSO), MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials in November 2016 together with reference checking and contact with study authors and experts in the field to identify additional studies.Selection criteria: We included randomised clinical trials comparing a freeze-all strategy with a conventional IVF/ICSI strategy which includes fresh transfer of embryos in women undergoing IVF or ICSI treatment.Data collection and analysis: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were cumulative live birth and OHSS. Secondary outcomes included other adverse effects (miscarriage rate).Main results: We included four randomised clinical trials analysing a total of 1892 women comparing a freeze-all strategy with a conventional IVF/ICSI strategy. The evidence was of moderate to low quality due to serious risk of bias and (for some outcomes) serious imprecision. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study, unit of analysis error, and absence of adequate study termination rules.There was no clear evidence of a difference in cumulative live birth rate between the freeze-all strategy and the conventional IVF/ICSI strategy (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.91 to 1.31; 4 trials; 1892 women; I2 = 0%; moderate-quality evidence). This suggests that if the cumulative live birth rate is 58% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 56% and 65%.The prevalence of OHSS was lower after the freeze-all strategy compared to the conventional IVF/ICSI strategy (OR 0.24, 95% CI 0.15 to 0.38; 2 trials; 1633 women; I2 = 0%; low-quality evidence). This suggests that if the OHSS rate is 7% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 1% and 3%.The freeze-all strategy was associated with fewer miscarriages (OR 0.67, 95% CI 0.52 to 0.86; 4 trials; 1892 women; I2 = 0%; low-quality evidence) and a higher rate of pregnancy complications (OR 1.44, 95% CI 1.08 to 1.92; 2 trials; 1633 women; low-quality evidence). There was no difference in multiple pregnancies per woman after the first transfer (OR 1.11, 95% CI 0.85 to 1.44; 2 trials; 1630 women; low-quality evidence), and no data were reported for time to pregnancy.Authors' conclusions: We found moderate-quality evidence showing that one strategy is not superior to the other in terms of cumulative live birth rates. Time to pregnancy was not reported, but it can be assumed to be shorter using a conventional IVF/ICSI strategy in the case of similar cumulative live birth rates, as embryo transfer is delayed